Extracellular adenosine 5′-triphosphate (ATP) has significant effects on a variety of pathological conditions and it is the main physiological agonist of P2X7 purinergic receptor (P2X7R). It is known ...that ATP acting via purinergic receptors plays a relevant role on skin inflammation, and P2X7R is required to neutrophil recruitment in a mice model of irritant contact dermatitis (ICD).The present study investigated the effects of chemical irritant croton oil (CrO) upon ATP, ADP, and AMP hydrolysis in mice blood serum, and the potential involvement of P2X7R. The topical application CrO induced a decrease on soluble ATP/ADPase activities (~50 %), and the treatment with the selective P2X7R antagonist, A438079, reversed these effects to control level. Furthermore, we showed that CrO decreased cellular viability (52.6 % ± 3.9) in relation to the control and caused necrosis in keratinocytes (PI positive cells). The necrosis induced by CrO was prevented by the pre-treatment with the selective P2X7R antagonist A438079. The results presented herein suggest that CrO exerts an inhibitory effect on the activity of ATPDase in mouse serum, reinforcing the idea that ICD has a pathogenic mechanism dependent of CD39. Furthermore, it is tempting to suggest that P2X7R may act as a controller of the extracellular levels of ATP.
ABSTRACT
Objectives Conflicting evidence indicates an increased risk for cardiovascular disease in postmenopausal women suffering from hot flushes. In this study, we tested whether, beyond hot ...flushes, menopausal symptoms are associated with biochemical and biophysical risk factors for cardiovascular disease.
Methods Retrospective cross-sectional analysis on 951 women in surgical or physiological postmenopause, recruited at the menopause outpatient service of our university hospital between April 2002 and December 2009. The Greene Climacteric Scale and its subscales for anxiety, depression, somatic symptoms, vasomotor symptoms and sexuality were used to evaluate menopausal complaints. Blood pressure, fasting glucose and lipids levels were evaluated as risk factors for cardiovascular disease. Anthropometric parameters and those derived by remote and reproductive medical history were used as possible confounders. All data were anonymously retrieved from an electronic database.
Results By multiple regression analysis, high density lipoprotein (HDL) cholesterol was inversely related to body mass index, the Greene Climacteric Scale score and years since menopause (R = 0.390; p = 0.0001). The total cholesterol/HDL cholesterol ratio was positively related to waist circumference and the Greene Climacteric Scale score (R = 0.356; p = 0.0001). Triglycerides (R = 0.353; p = 0.0001) and triglyceride/HDL cholesterol (R = 0.425; p = 0.0001) were positively related to waist circumference, the Greene Climacteric Scale score and the Greene vasomotor subscore. Glucose was positively related to waist circumference, years since menopause and the Greene Climacteric Scale score (R = 0.390; p = 0.0001). Blood pressure was not related to menopausal symptoms. The 10-year risk for cardiovascular disease calculated by the Framingham formula was related independently and directly to body mass index and the Greene Climacteric Scale score (R = 0.183; p = 0.0001).
Conclusions Menopausal symptoms evaluated by a validated climacteric scale are associated with a worsening of biochemical risk factors for atherosclerosis and cardiovascular disease.
We present the AGILE-GRID (Astro-rivelatore Gamma a Immagini LEggero – Gamma-Ray Imaging Detector) monitoring of Cygnus X-3, during the period between November 2007 and July 2009. We report here the ...whole AGILE-GRID monitoring of Cygnus X-3 in the AGILE “pointing” mode data-taking, to confirm that the γ-ray activity coincides with the same repetitive pattern of multiwavelength emission and analyze in depth the overall γ-ray spectrum by assuming both leptonic and hadronic scenarios. Seven intense γ-ray events were detected in this period, with a typical event lasting one or two days. These durations are longer than the likely cooling times of the γ-ray emitting particles, implying we see continuous acceleration rather than the result of an impulsive event such as the ejection of a single plasmoid that then cools as it propagates outwards. Cross-correlating the AGILE-GRID light curve with both X-ray and radio monitoring data, we find that the main events of γ-ray activity were detected while the system was in soft spectral X-ray states (RXTE/ASM (Rossi X-ray Timing Explorer/All-Sky Monitor)count rate in the 3−5 keV band ≳ 3 counts s-1), that coincide with local and often sharp minima of the hard X-ray flux (Swift/BAT (Burst Alert Telescope) count rate ≲0.02 counts cm-2 s-1), a few days before intense radio outbursts. This repetitive temporal coincidence between the γ-ray transient emission and spectral state changes of the source turns out to be the spectral signature of γ-ray activity from this microquasar. These γ-ray events may thus reflect a sharp transition in the structure of the accretion disk and its corona, which leads to a rebirth of the microquasar jet and subsequent enhanced activity in the radio band. The γ-ray differential spectrum of Cygnus X-3 (100 MeV–3 GeV), which was obtained by averaging the data collected by the AGILE-GRID during the γ-ray events, is consistent with a power law of photon index α = 2.0±0.2. Finally, we examine leptonic and hadronic emission models for the γ-ray events and find that both scenarios are valid. In the leptonic model – based on inverse Compton scatterings of mildly relativistic electrons on soft photons from both the Wolf-Rayet companion star and the accretion disk – the emitting particles may also contribute to the overall hard X-ray spectrum, possibly explaining the hard non-thermal power-law tail seen during special soft X-ray states in Cygnus X-3.
Kinins and their receptors have been recently implicated in cancer. Using functional and molecular approaches, we investigated the relevance of kinin B1 and B2 receptors in bladder cancer. Functional ...studies were conducted using bladder cancer cell lines, and human biopsies were employed for molecular studies. Both B1 des-Arg(9)-BK and B2 BK receptor agonists stimulated the proliferation of grade 3-derived T24 bladder cancer cells. Furthermore, treatment with B1 and B2 receptor antagonists (SSR240612 and HOE140) markedly inhibited the proliferation of T24 cells. Only higher concentrations of BK increased the proliferation of the grade 1 bladder cancer cell line RT4, while des-Arg(9)-BK completely failed to induce its proliferation. Real-time PCR revealed that the mRNA expression of kinin receptors, particularly B1 receptors, was increased in T24 cells relative to RT4 cells. Data from bladder cancer human biopsies revealed that B1 receptor expression was increased in all tumor samples and under conditions of chronic inflammation. We also show novel evidence demonstrating that the pharmacological inhibition of PI3Kγ (phosphatidylinositol 3-kinase) with AS252424, concentration-dependently reduced T24 cell proliferation induced by BK or des-Arg(9)-BK. Finally, the incubation of T24 cells with kinin agonists led to a marked activation of the PI3K/AKT and ERK 1/2 signaling pathways, whereas p38 MAP kinase remained unaffected. Kinin receptors, especially B1 receptors, appear to be implicated in bladder cancer progression. It is tempting to suggest that selective kinin antagonists might represent potential alternative therapies for bladder cancer.
Aims. We probe the high-energy (>60 MeV) emission from the black hole X-ray binary system, Cygnus X-1, and investigate its origin. Methods. We analyzed 7.5 yr of data by Fermi-LAT with the latest ...Pass 8 software version. Results. We report the detection of a signal at ~8σ statistical significance that is spatially coincident with Cygnus X-1 and has a luminosity of 5.5 × 1033 erg s-1, above 60 MeV. The signal is correlated with the hard X-ray flux: the source is observed at high energies only during the hard X-ray spectral state, when the source is known to display persistent, relativistic radio-emitting jets. The energy spectrum, extending up to ~20 GeV without any sign of spectral break, is well fit by a power-law function with a photon index of 2.3 ± 0.2. There is a hint of orbital flux variability, with high-energy emission mostly coming around the superior conjunction. Conclusions. We detected GeV emission from Cygnus X-1 and probed that the emission is most likely associated with the relativistic jets. The evidence of flux orbital variability indicates the anisotropic inverse-Compton on stellar photons as the mechanism at work, thus constraining the emission region to a distance 1011–1013 cm from the black hole.
A quercetina é um flavonoide, amplamente encontrada em frutas, vegetais, grãos, flores, com elevada concentração no vinho tinto, e tem sido caracterizada funcionalmente pela atividade antioxidante. ...Para avaliação da maturação nuclear e do desenvolvimento embrionário bovino, os oócitos foram maturados por 22h na presença de quercetina (0,4, 2, 10 e 50µM), cisteamina (100µM) e na ausência dos antioxidantes. Os oócitos maturados foram corados com Hoechst para avaliação da maturação in vitro. Para avaliação do desenvolvimento embrionário, os oócitos foram fertilizados e cultivados in vitro, as taxas de desenvolvimento embrionário foram determinadas no sétimo dia de cultivo e o percentual de eclosão e o número de células dos embriões no oitavo dia. Os níveis de glutationa (GSH) dos oócitos foram mensurados por emissão de fluorescência com CMF2HC. A porcentagem de maturação nuclear (±89%) não diferiu entre os grupos. O desenvolvimento embrionário variou entre os tratamentos, o percentual de blastocisto foi superior (P<0,05) nos grupos tratados com 0,4, 2, 10 e 50∝M de quercetina (56,9, 59,5, 53,6 e 49,6%, respectivamente) e com 100∝M de cisteamina (50,4%) em relação ao grupo controle (42,3%). Na comparação entre os dois antioxidantes, a quercetina (0,4 e 2µM) foi superior na produção de embriões (56,9 e 59,5%, respectivamente) em comparação com cisteamina (50,4%). As taxas de embriões eclodidos foram similares (P>0,05) entre os grupos (±63,0%). O número médio de células dos embriões também foi similar entre os grupos (±233). Os níveis intracelulares de GSH foram superiores nos oócitos maturados com cisteamina, mas similares entre os oócitos tratados com quercetina e o controle. A suplementação da maturação in vitro com antioxidantes melhora as taxas de blastocistos. A quercetina foi superior à cisteamina, que, por sua vez, foi superior ao controle. Mas os níveis de GSH foram superiores somente nos oócitos tratados com cisteamina.
Summary
Kinins and their receptors have been recently implicated in cancer. Using functional and molecular approaches, we investigated the relevance of kinin B
1
and B
2
receptors in bladder cancer. ...Functional studies were conducted using bladder cancer cell lines, and human biopsies were employed for molecular studies. Both B
1
des-Arg
9
-BK and B
2
BK receptor agonists stimulated the proliferation of grade 3-derived T24 bladder cancer cells. Furthermore, treatment with B
1
and B
2
receptor antagonists (SSR240612 and HOE140) markedly inhibited the proliferation of T24 cells. Only higher concentrations of BK increased the proliferation of the grade 1 bladder cancer cell line RT4, while des-Arg
9
-BK completely failed to induce its proliferation. Real-time PCR revealed that the mRNA expression of kinin receptors, particularly B
1
receptors, was increased in T24 cells relative to RT4 cells. Data from bladder cancer human biopsies revealed that B
1
receptor expression was increased in all tumor samples and under conditions of chronic inflammation. We also show novel evidence demonstrating that the pharmacological inhibition of PI3Kγ (phosphatidylinositol 3-kinase) with AS252424, concentration-dependently reduced T24 cell proliferation induced by BK or des-Arg
9
-BK. Finally, the incubation of T24 cells with kinin agonists led to a marked activation of the PI3K/AKT and ERK 1/2 signaling pathways, whereas p38 MAP kinase remained unaffected. Kinin receptors, especially B
1
receptors, appear to be implicated in bladder cancer progression. It is tempting to suggest that selective kinin antagonists might represent potential alternative therapies for bladder cancer.
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